CN105753820B - A kind of method of purification of dehydroandrographolide succinate - Google Patents
A kind of method of purification of dehydroandrographolide succinate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
Abstract
The invention provides a kind of new method of purification of dehydroandrographolide succinate.Using dehydroandrographolide succinate or its pharmaceutically acceptable salt as purifying object, under inert gas shielding, dehydroandrographolide succinate or its pharmaceutically acceptable salt are suspended in the mixed system of water and specific organic solvent composition, control above-mentioned mixed system temperature, pass through the pH value of regulation system to acidity, dehydroandrographolide succinate is set to distribute into organic phase, liquid separation is simultaneously washed, take organic phase, it is concentrated under reduced pressure, obtain dehydroandrographolide succinate concentrate, above-mentioned concentrate is crystallized, filter and dry, the sterling of the compound is prepared.The dehydroandrographolide succinate purity obtained using this method is high, good fluidity.It can be widely applied to the purification and recycling of dehydroandrographolide succinate and its pharmaceutically acceptable salt.
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to the method for purification that a kind of medicine is new, and in particular to a kind of new
Dehydroandrographolide succinate method of purification.
Background technology
Herba Andrographitis is the herb of acanthaceous plant Herba Andrographitis (Andrographis paniculata (Burm.F.) Nees)
Or leaf.Also known as Chun Lianqiuliu, Banlangen, Euphorbia, andrographis paniculata, golden vanilla, golden tack, India's grass, eel grass etc..There is heat-clearing solution
Poison, anti-inflammatory, swelling and pain relieving effect.Cure mainly bacillary dysentery, urinary tract infections, acute tonsillitis, enteritis, sphagitis, pneumonia and
Influenza etc., external application can treat sore furuncle poison, trauma infection contamination etc..Main product saves in Guangdong, Fujian etc., Central China, North China, northwest
Etc. ground also introduce a fine variety.
Dehydro and drographolide diacid half esters and its derivative, its representative species andrographolide, English name Potassium
Sodium Dehydroandroandrographolide Succinate, chemical name are that the dehydrogenations of 14- deshydroxies -11,12- two are worn
Heart lotus lactone -3,19- disuccinic acid half ester k-na salt, there is heat-clearing, anti-inflammation is antiviral to wait pharmacological action, has Chinese medicine " anti-
The title of raw element ".At present andrographolide all as intermediate (compound shown in Formulas I) through being prepared into salt.
Document [1] _ Hu Tugao, Bai Jun, Liu Yan at present, Anhui Prov. Inst. of Pharmacology Dehydro and drographolide disuccinic acids
Improvement in synthesis [J] the Anhui medicine of half ester, 2006 (10):3；[2] _ Traditional Chinese Medicine Research Institute, Sichuan Province Yao Hua rooms Herba Andrographitis is ground
Study carefully research [J] the Chinese herbal medicines communication of group POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATEs and its parenteral solution, 1978 (8):1；
[3] _ CN1927854A, [4] _ Zhou Huijin are even beautiful, improvement in synthesis and the key of dehydroandrographolide succinate
Technology controlling and process point [J], Heilungkiang scientific and technological information, 2009 (10):72-73；[5]_CN102863408A,[6]_
CN102617527A；[7] synthesising process research of _ potassium dehydroandrographolide succinate, Hou Qianqian, He'nan Normal University, 2014.Preparation reported above
The method of compound of formula I is as follows：
The above method is used as solvent and catalysis using andrographolide and succinic anhydride as raw material, using pyridine or other organic bases
Agent or acid binding agent, and under antioxidant anhydrous sodium sulfite or inert gas shielding, heating or back flow reaction, then using a large amount of
Sour water or moisture separate out intermediate dehydroandrographolide succinate (Formulas I), and it is ripe to reuse those skilled in the art institute
The sodium carbonate known, potassium carbonate, or sodium acid carbonate, saleratus divides one-step or two-step into natrium potassium salt, and then obtains andrographolide.
Document [1] Hu Tugao, Bai Jun, Liu Yan at present, Anhui Prov. Inst. of Pharmacology Dehydro and drographolides disuccinic acid half
Improvement in synthesis [J] the Anhui medicine of ester, 2006 (10):3；[2] _ Traditional Chinese Medicine Research Institute, Sichuan Province Yao Hua rooms Herba Andrographitis research
The communication of research [J] the Chinese herbal medicines of group POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATEs and its parenteral solution, 1978 (8):1；
[3] _ CN1927854A, [4] _ Zhou Huijin are even beautiful, improvement in synthesis and the key of dehydroandrographolide succinate
Technology controlling and process point [J], Heilungkiang scientific and technological information, 2009 (10):72-73；[5]_CN102863408A,[6]_
CN102617527A；[7] synthesising process research of _ potassium dehydroandrographolide succinate, Hou Qianqian, He'nan Normal University, 2014；[8]_Xin-Feng
Luo,Ling He,Hai-BinYin et al.Efficient Acylation and One-Pot Synthesisof
Dehydroandrographolide Succinate on a Large Scale Assisted with Microwave
Radiation[J],Synthetic Communications,39:3444–3452,2009；Formula I chemical combination reported above
The method of thing is as follows：
The above method is used as solvent and catalysis using andrographolide and succinic anhydride as raw material, using pyridine or other organic bases
Agent or acid binding agent, and under antioxidant anhydrous sodium sulfite or inert gas shielding, heating or back flow reaction, then using a large amount of
Sour water or moisture separate out intermediate dehydroandrographolide succinate (Formulas I), and it is ripe to reuse those skilled in the art institute
The sodium carbonate known, potassium carbonate, or sodium acid carbonate, saleratus divides one-step or two-step into natrium potassium salt, and then obtains andrographolide.
At present, for above method during formula I, isolating and purifying Formulas I mainly has following several method：
1. dispersion method：Document [3], [4], [6], the method that [8] use is dispersion method, and concrete operations are：Using formula (I) and
Its pyridiniujm, the property almost do not allowed in pure water or in sour water existing for a small amount of acid.Formula (I) after completion of the reaction anti-will be prepared
Liquid is answered, is poured into the water or aqueous acid of certain volume, or the water of certain volume or sour water are added to after completion of the reaction
In reaction solution, because formula (I) is fat-soluble big, water is practically insoluble in.Be poured into or dropwise operation during can separate out solid, it is such a
Though method can be readily available formula (I) solid.But in actual production operating process, following problem be present：First, formula (I) is several
Characteristic not soluble in water, causes in crystallization process, degree of supersaturation narrow range, and in crystallization process, concentration gradient is small, is poured into
The solid generated during water or dropwise addition water is all made up of minimum nucleus.The growth for not having nucleus becomes big process.So as to
Cause finally to produce that a large amount of particles are superfine, the big formula of specific surface area (I) solid, the solvent of such a solid not only absorption parcel itself
And impurity is more, product purity is not high.And follow-up filtering is given, dry zone carrys out very big challenge.Second, during preparing formula (I),
Caused various impurity include reaction initiation material, and intermediates are all essentially oil-soluble impurities, not soluble in water.Thus use
Formula (I) solid that dispersion method obtains, and can not up to remove the purpose of oil-soluble impurities caused by reaction.Need to be by follow-up
Operation is further purified.
2. crystallisation：Document [1], [2], the method that [7] use is dispersion method, and concrete operations are：Dispersion method is obtained
Formula (I) solid (crude product) is recrystallized using absolute methanol or ethanol.The refined yield of its Literature [1] only has 41.7%,
Document [2] does not have yield data.Document [7] does not obtain solid when using ethyl alcohol recrystallization.With greater need for being mentioned that, document [7]
The operation of solid is obtained using absolute methanol, is in -25~-20 freezings, separates out solid.But the operation of later separation solid-liquid is not
Filtering or centrifugation, but use the method for low temperature drying to remove methanol.Really a low temperature is concentrated and dried the mistake for obtaining solid
Journey, it is not recrystallization process.Let alone remove the purpose of impurity.All waved unless producing impurity during preparing formula (I)
Hair property, this is clearly unpractical.The Primary Study carried out according to document [7] and the present inventor shows that formula (I) is being tested
Room, which is often used in organic solvent, has very big solubility, formula (I) at alcohols (methanol, ethanol, isopropanol, n-butanol, the tert-butyl alcohol),
Esters (Ethyl formate, methyl acetate, ethyl acetate), halogenated hydrocarbons (dichloromethane, chloroform), ketone (acetone, butanone), ether or
Cyclic ethers class (glycol dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, anisole), nitrile (acetonitrile, propionitrile), acyl
Dissolving in the above solvent such as amine (formamide, DMF), sour or alkali (formic acid, acetic acid, triethylamine, pyridine)
Both less than 1g/5mL, part under normal temperature is spent to be even less than 1g/3mL and also almost can not analyse crystal even if being cooled to 0 DEG C.Document [7]
The experiment that Hou Qianqian (being shown in Table 1) is recrystallized to following solvent is attempted also to demonstrate this point.
Table one：Formula (I) recrystallization solvent screening situation of document report
| Solvent | Products therefrom |
| Water | Clear yellow viscous material |
| Glacial acetic acid | Clear yellow viscous material |
| Ethanol | Clear yellow viscous material |
| Acetone | Yellow oily material |
| Methanol | Yellow oily material |
| Ethyl acetate | Yellow oily material |
| Chloroform | Yellow oily material |
| Isopropanol | Separated out without any material |
To sum up, at present using above method preparative separation purification formula (I) compound, due to the limit of theoretical and big production practices
System, though partial parameters can be optimized and carried out with solvent screening replacement, but still can not overcome and first use water or sour water, or
Other almost insoluble appearance solvent first disperse acquisition formula (I) solid.By subsequently carrying out weight into salt or use above solvent system
Crystallization.These a large amount of cumbersome and time-consuming technological operations, not only reduce production efficiency, cannot guarantee that acquisition is in high yield and high-quality
The product of amount, thus caused by waste be surprising.For a kind of this urgently new technical scheme, to provide more excellent technique bar
Part, the quality of product is improved, is raised labour productivity, reduces production cost to greatest extent, it is more beneficial for extensive work
Industry separating-purifying or recovery formula (I).
The content of the invention
To overcome prior art defect, it is an object of the invention to provide a kind of dehydroandrographolide succinate
Method of purification, using dehydroandrographolide succinate or its pharmaceutically acceptable salt as purifying object, in indifferent gas
Under body protection, dehydroandrographolide succinate or its pharmaceutically acceptable salt are suspended in water and specific organic molten
In the mixed system of agent composition, above-mentioned mixed system temperature is controlled, by the pH value of regulation system to acidity, makes dehydration Herba Andrographitis
Lactone disuccinic acid half ester is distributed into organic phase, and liquid separation is simultaneously washed, and is taken organic phase, is concentrated under reduced pressure into certain volume, must be dehydrated
Andrographolide disuccinic acid half ester concentrate, above-mentioned concentrate is crystallized, and is filtered and is dried, and is prepared in dehydration Herba Andrographitis
The sterling of ester disuccinic acid half ester, shown in the compound such as formula (I)：
Preferably, described dehydroandrographolide succinate pharmaceutically acceptable salt is selected from：It is dehydrated punching
Lotus lactone disuccinic acid half ester alkali metal salt and/or its mixture, dehydroandrographolide succinate alkali salt
And/or its mixture, any one in dehydroandrographolide succinate ammonium salt and/or its mixture.
It is further preferred that dehydroandrographolide succinate alkali metal salt is selected from：Dehydro and drographolide two
The mono-sodium salt or double sodium salt of succinic acid half-ester, the monopotassium salt of dehydroandrographolide succinate or double sylvite, dehydration are worn
What the single lithium salts or double lithium salts of heart lotus lactone disuccinic acid half ester or more three kinds of alkali metal stoichiometrically formed with free acid
Any one in salt-mixture.
It is further preferred that the dehydroandrographolide succinate alkali salt is selected from：Magnesium salts, calcium salt,
Any one in strontium salt or barium salt.
It is further preferred that the dehydroandrographolide succinate ammonium salt is selected from：Its pyridiniujm, its amino acid
Salt, its carbon atoms are C1-C10Aliphatic the small molecule amine ammonium salt and/or its salt-mixture that are combined with free acid in it is any one
Kind.
Preferably, the dehydroandrographolide succinate or its pharmaceutically acceptable salt purity are more than
80%；Preferably, purity >=90%；It is further preferred that purity >=95%；It is furthermore preferred that purity >=98.0%.
Preferably, described pH value is 3.0-6.0.
Preferably, the inert gas is selected from nitrogen or argon gas.
Preferably, the dehydroandrographolide succinate or the rate of charge of its pharmaceutically acceptable salt and water
Example is 1:10~80 (m/V, unit g/mL)；It is further preferred that ingredient proportion is 1:10~60 (m/V, unit g/mL).
Preferably, the dehydroandrographolide succinate or its pharmaceutically acceptable salt and organic solvent
Ingredient proportion is 1:10~80 (m/V, g/mL)；It is further preferred that ingredient proportion is 1:15~60 (m/V, g/mL).
Preferably, described specific organic solvent is selected from：N-propyl acetate, isopropyl acetate, butyl acetate, propionic acid second
Any one in ester, ethyl butyrate, propyl formate, isopropyl formate, butyl formate；It is it is further preferred that described organic molten
Agent is n-propyl acetate, isopropyl acetate or butyl acetate.
Preferably, the acid for being used to adjust pH value is the organic acid or inorganic acid of Pka≤5, and its concentration range is
0.05mol/L~12mol/L；Preferably, described acid is hydrochloric acid.
Preferably, the temperature of the regulation pH value is -10~40 DEG C；It is further preferred that temperature is 0~20 DEG C；It is more excellent
Choosing, temperature is 8~12 DEG C；Most preferably, temperature is 10 ± 2 DEG C.
Preferably, in the dehydroandrographolide succinate concentrate, Dehydro and drographolide disuccinic acid
The ratio of half ester and organic solvent is 1:2~50 (m/V, g/mL)；It is further preferred that Dehydro and drographolide disuccinic acid half
The ratio of ester and organic solvent is 1:5~30 (m/V, g/mL).
Compared with prior art, the technological merit of the present invention program is embodied in the following aspects：
1st, one of key of the invention is the technical side of separating-purifying dehydroandrographolide succinate (Formulas I)
Case, applicability is wide, can not only refine dehydroandrographolide succinate (free acid) crude product, also can be directly used for dense
Reaction solution separating-purifying after contracting, can also be used for dehydroandrographolide succinate pharmaceutically-acceptable salts recovery or
Person purifies.Avoid and use prior art, recovery dehydroandrographolide succinate pharmaceutically-acceptable salts are (such as
Andrographolide) need to use high temperature concentration alcohol solution method caused by considerable part product degrade the problem of.
2nd, the two of key of the invention are to prepare purification ＆ isolation dehydroandrographolide succinate (Formulas I) process
In, water-solubility impurity and oil-soluble impurities can be removed by washing and organic solvent recrystallization respectively, thus using such a
Methods For Purification or the dehydroandrographolide succinate of recovery can reach very high purity.And the technology provided at present
Scheme (including dispersion method and recrystallization method) and unresolved this problem of removal oil-soluble impurities.
3rd, the three of key of the invention are to prepare purification ＆ isolation dehydroandrographolide succinate (Formulas I) process
In, have been surprisingly found that under dehydroandrographolide succinate (Formulas I) normal temperature in n-propyl acetate, isopropyl acetate, acetic acid
Solubility in butyl ester equal solvent between 1g/15-60mL, and solubility can variation with temperature and change.Thus crystallization work
Skill procedure parameter design space and scope are wide, comparable to be readily available that particle is big, and specific surface area is small, easily filter and separation is consolidated
Body crystallizes.It should be noted that above solvent is all the not high organic solvent of volatile boiling point, it is very easy to that place is dried
Reason.
The four of the key of the present invention are during purification ＆ isolation dehydroandrographolide succinate (Formulas I), anticipate
The outer foreign pigment for finding to bring into reaction or crude product, has good solubility, recrystallization process in above organic solvent
In need not carry out any decolorization.Influenceing the impurity of product colour can also be removed by using above solvent recrystallization, be entered
One step simplifies operation sequence.
This method has applicability wide, and mild condition, raw material is low with reagent toxicity, isolates and purifies that process is simple, and product is easy
In filtering and dry, product quality is high.It is especially suitable for industrial-scale production.
Brief description of the drawings
Fig. 1 is the structural formula of dehydroandrographolide succinate；
Fig. 2 is the route map of purification dehydroandrographolide succinate, wherein
Represent the salt of dehydroandrographolide succinate, A+Or B+Represent certain cation.
Embodiment
To make the object, technical solutions and advantages of the present invention of greater clarity, with reference to embodiment and join
According to accompanying drawing, the present invention is described in more detail.It should be understood that these descriptions are merely illustrative, and it is not intended to limit this hair
Bright scope.
Embodiment one：
Under inert gas shielding, dehydroandrographolide succinate 30g (purity is added into reaction bulb：
92.34%), n-propyl acetate 600ml.45 DEG C are warming up to, stirring and dissolving clarification.Purified water 600ml is added, is cooled to 10-15
DEG C, 0.5mol/L hydrochloric acid solutions are added dropwise and adjust PH to 3.5.Stratification, separate organic layer.Organic layer is washed with purified water 100ml
Once, organic layer is separated, 10 times (volume specific mass, V/M, calculating of weighing) of material is concentrated under reduced pressure into, is cooled to 0 ± 2 DEG C and stirs
Mix crystallization 2 hours.Filtering, is washed with 0-5 DEG C of n-propyl acetate 30ml, obtains white solid 26.4g, yield 88.0%, purity：
98.45%.
Embodiment two：
Under the protection of inert gas, andrographolide 30g, succinic anhydride 45g, pyridine 75ml are added into reaction bulb.
80 DEG C are warming up to, stirring reaction 5 hours.Reaction finishes (sampling detection reaction solution purity：89.67%), it is concentrated under reduced pressure and steams pyrrole
Pyridine.Isopropyl acetate 1125ml is added into residue, stirring and dissolving, adds purified water 675ml.15-20 DEG C of temperature control, it is added dropwise
2mol/L hydrochloric acid solutions adjust PH to 3.0.Stratification, separate organic layer.Organic layer washed once with purified water 200ml, separate
Organic layer, 12 times (volume specific mass, V/M, calculating of weighing) of material are concentrated under reduced pressure into, it is small to be cooled to 0-5 DEG C of stirring and crystallizing 2
When.Filtering, is washed with 0-5 DEG C of isopropyl acetate 40ml, obtains white solid 39.2g, yield 86.0%, purity：98.02%.
Embodiment three：
Under inert gas shielding, andrographolide 20g (purity is added into reaction bulb：98.21%), purified water 240ml, room
The lower stirring and dissolving clarification of temperature.Isopropyl acetate 360ml is added, is cooled to 0-5 DEG C, 0.5mol/L hydrochloric acid solutions are added dropwise and adjust PH extremely
4.0, it is during which visible to there is white mass precipitation then to dissolve.Stratification, separate organic layer.Organic layer is washed with purified water 80ml
Once, organic layer is separated, 8 times (volume specific mass, V/M, calculating of weighing) of material is concentrated under reduced pressure into, is cooled to 0 ± 2 DEG C of stirring
Crystallization 2 hours.Filtering, is washed with 0-5 DEG C of isopropyl acetate 20ml, obtains white solid 16.5g, yield 91.7%, purity：
99.60%.
Example IV：
Under inert gas shielding, it is (pure that dehydroandrographolide succinate disodium salt 60g is added into reaction bulb
Degree：98.68%), purified water 600ml.25-35 DEG C of temperature control, stirring and dissolving clarification.N-butyl acetate 2010ml is added, is cooled to 5
± 2 DEG C, 1mol/L hydrochloric acid solutions are added dropwise and adjust PH to 4.5, it is during which visible to there is white mass precipitation then to dissolve.Stratification, point
Go out organic layer.Organic layer washed once with purified water 200ml, separate organic layer, be concentrated under reduced pressure into 15 times of (volume ratio matter of material
Amount, V/M, calculating of weighing), it is cooled to 5 ± 2 DEG C of stirring and crystallizings 2 hours.Filtering, is washed with 0-5 DEG C of n-butyl acetate 50ml,
Obtain white solid 40.0g, yield 90.0%, purity：99.56%.
Embodiment five：
Under inert gas shielding, it is (pure that dehydroandrographolide succinate calcium salt 30g is added into reaction bulb
Degree：98.01%), purified water 750ml, it is dispersed with stirring at room temperature, in suspended state.Isopropyl acetate 900ml is added, is cooled to
10 ± 2 DEG C, 1mol/L hydrochloric acid solutions are added dropwise and adjust PH to 3.7, stratification, separate organic layer.Organic layer is washed with purified water 100ml
Wash once, separate organic layer, be concentrated under reduced pressure into 10 times (volume specific mass, V/M, calculating of weighing) of material, be cooled to 5 ± 2 DEG C
Stirring and crystallizing 2 hours.Filtering, is washed with 0-5 DEG C of isopropyl acetate 20ml, obtains white solid 25.8g, yield 92.1% is pure
Degree：99.48%.
Embodiment six：
Under inert gas shielding, potassium dehydroandrographolide succinate 50g (purity is added into reaction bulb：97.36%), purified water 750ml, room
It is dispersed with stirring under temperature, in suspended state.Isopropyl acetate 1000ml is added, is cooled to 5 ± 2 DEG C, it is molten that 0.5mol/L hydrochloric acid is added dropwise
Liquid adjusts PH to 3.5, stratification, separates organic layer.Organic layer washed once with purified water 100ml, separate organic layer, and decompression is dense
6 times (volume specific mass, V/M, calculating of weighing) of material are reduced to, are cooled to 0 ± 2 DEG C of stirring and crystallizing 2 hours.Filtering, with 0-5 DEG C
Isopropyl acetate 50ml washing, obtain white solid 43.5g, yield 93.0%, purity：98.95%.
Claims (24)
1. a kind of method of purification of dehydroandrographolide succinate, it is characterised in that with Dehydro and drographolide two
Succinic acid half-ester or its pharmaceutically acceptable salt are purifying object, under inert gas shielding, by Dehydro and drographolide two
Succinic acid half-ester or its pharmaceutically acceptable salt are suspended in the mixed system of water and specific organic solvent composition, and control is above-mentioned
Mixed system temperature, by the pH value of regulation system to acidity, dehydroandrographolide succinate is set to distribute to organic
Xiang Zhong, liquid separation are simultaneously washed, take organic phase, be concentrated under reduced pressure into certain volume, obtain dehydroandrographolide succinate concentration
Liquid, above-mentioned concentrate is crystallized, filter and dry, the sterling of dehydroandrographolide succinate, dehydration is prepared
Shown in andrographolide disuccinic acid half ester such as formula (I)：
Wherein, described specific organic solvent is selected from：N-propyl acetate, isopropyl acetate, butyl acetate, ethyl propionate, butyric acid
Any one in ethyl ester, propyl formate, isopropyl formate, butyl formate.
2. method of purification according to claim 1, it is characterised in that described specific organic solvent be n-propyl acetate,
Isopropyl acetate or butyl acetate.
3. method of purification according to claim 1 or 2, it is characterised in that described Dehydro and drographolide disuccinic acid
Half ester pharmaceutically acceptable salt is selected from：Dehydroandrographolide succinate alkali metal salt and/or its mixture, dehydration
Andrographolide disuccinic acid half ester alkali salt and/or its mixture, dehydroandrographolide succinate ammonium salt
And/or any one in its mixture.
4. method of purification according to claim 3, it is characterised in that dehydroandrographolide succinate alkali metal
Salt is selected from：The mono-sodium salt or double sodium salt of dehydroandrographolide succinate, dehydroandrographolide succinate
Monopotassium salt or double sylvite, three kinds of alkali metal of single lithium salts of dehydroandrographolide succinate or double lithium salts or more with
Any one in the salt-mixture that free acid stoichiometrically forms.
5. method of purification according to claim 3, it is characterised in that the dehydroandrographolide succinate alkali
Earth metal salt is selected from：Any one in magnesium salts, calcium salt, strontium salt or barium salt.
6. method of purification according to claim 3, it is characterised in that the dehydroandrographolide succinate ammonium
Salt is selected from：Its pyridiniujm, its amino-acid salt, its carbon atoms are C1-C10The ammonium that is combined with free acid of aliphatic small molecule amine
Any one in salt and/or its salt-mixture.
7. according to the method for purification described in claim 1-2,4-6 any one, it is characterised in that the purity of the purifying object
More than 80%.
8. method of purification according to claim 7, it is characterised in that purity >=90% of the purifying object.
9. method of purification according to claim 8, it is characterised in that purity >=95% of the purifying object.
10. method of purification according to claim 9, it is characterised in that purity >=98% of the purifying object.
11. method of purification according to claim 1, it is characterised in that described pH value is 3.0-6.0.
12. method of purification according to claim 1, it is characterised in that the inert gas is selected from nitrogen or argon gas.
13. method of purification according to claim 1, it is characterised in that the dehydroandrographolide succinate
Or the ingredient proportion of its pharmaceutically acceptable salt and water is m/V, unit g/mL, concrete numerical value 1:10~80.
14. method of purification according to claim 13, it is characterised in that the dehydroandrographolide succinate
Or the ingredient proportion of its pharmaceutically acceptable salt and water is m/V, unit g/mL, concrete numerical value 1:10~60.
15. method of purification according to claim 1, it is characterised in that the dehydroandrographolide succinate
Or the ingredient proportion of its pharmaceutically acceptable salt and organic solvent is m/V, unit g/mL, concrete numerical value 1:10~80.
16. method of purification according to claim 15, it is characterised in that the dehydroandrographolide succinate
Or the ingredient proportion of its pharmaceutically acceptable salt and organic solvent is m/V, unit g/mL, concrete numerical value 1:15~60.
17. the method for purification according to claim 1 or 11, it is characterised in that it is described be used to adjusting the acid of pH value for Pka≤
5 organic acid or inorganic acid, and its concentration range is 0.05mol/L~12mol/L.
18. method of purification according to claim 17, it is characterised in that described acid is hydrochloric acid.
19. the method for purification according to claim 1 or 11, it is characterised in that the temperature of the regulation pH value is -10~40
℃。
20. method of purification according to claim 19, it is characterised in that the temperature of the regulation pH value is 0~20 DEG C.
21. method of purification according to claim 20, it is characterised in that the temperature of the regulation pH value is 8~12 DEG C.
22. method of purification according to claim 21, it is characterised in that the temperature of the regulation pH value is 10 ± 2 DEG C.
23. method of purification according to claim 1, it is characterised in that the dehydroandrographolide succinate
In concentrate, the ratio of dehydroandrographolide succinate and organic solvent is m/V, unit g/mL, concrete numerical value
For 1:2~50.
24. method of purification according to claim 23, it is characterised in that the dehydroandrographolide succinate
Ratio with organic solvent is m/V, unit g/mL, concrete numerical value 1:5~30.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610178013.7A CN105753820B (en) | 2016-03-25 | 2016-03-25 | A kind of method of purification of dehydroandrographolide succinate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102367243A (en) * | 2011-08-26 | 2012-03-07 | 贺金凤 | Stable potassium sodium dehydroandroan drographolide succinate compound and pharmaceutical composition thereof |
| CN103087017A (en) * | 2013-02-28 | 2013-05-08 | 成都倍特药业有限公司 | Refinement method of crude potassium sodium dehydroandroan drographolide succinate product |
| CN104892552A (en) * | 2015-05-20 | 2015-09-09 | 河南师范大学 | Method for purifying dehydroandrographolide succinate |
| CN104945357A (en) * | 2015-06-09 | 2015-09-30 | 湖北荆楚理工科技开发有限公司 | Refining method of dehydroandrographolide succinate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102367243A (en) * | 2011-08-26 | 2012-03-07 | 贺金凤 | Stable potassium sodium dehydroandroan drographolide succinate compound and pharmaceutical composition thereof |
| CN103087017A (en) * | 2013-02-28 | 2013-05-08 | 成都倍特药业有限公司 | Refinement method of crude potassium sodium dehydroandroan drographolide succinate product |
| CN104892552A (en) * | 2015-05-20 | 2015-09-09 | 河南师范大学 | Method for purifying dehydroandrographolide succinate |
| CN104945357A (en) * | 2015-06-09 | 2015-09-30 | 湖北荆楚理工科技开发有限公司 | Refining method of dehydroandrographolide succinate |
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